1. Field of the Invention
The present invention relates to amidino compounds and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
2. Related Art
It has been known since the early 1980""s that the vascular relaxation caused by acetylcholine is dependent on the vascular endothelium. The endothelium-derived relaxing factor (EDRF), now known to be nitric oxide (NO) is generated in the vascular endothelium by nitric oxide synthase (NOS). The activity of NO as a vasodilator has been known for well over 100 years. In addition, NO is the active species deriving from amylnitrite, glyceryltrinitrate and other nitrovasodilators. The identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.
Nitric oxide is an endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system.
There are at least three types of NO synthase as follows:
(i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible nitric oxide synthase (hereinafter xe2x80x9ciNOSxe2x80x9d) generates NO continuously for long periods.
The NO released by each of the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the NO synthesized by iNOS.
There is a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place as a result of certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis.
Some of the NO synthase inhibitors proposed for therapeutic use are non-selective, they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, while non-selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
The following individual publications disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase:
PCT Patent Application No. WO 96/35677.
PCT Patent Application No. WO 96/33175.
PCT Patent Application No. WO 96/15120.
PCT Patent Application No. WO 95/11014.
PCT Patent Application No. WO 95/11231.
PCT Patent Application No. WO 99/46240.
PCT Patent Application No. WO 95/24382.
PCT Patent Application No. WO 94/12165.
PCT Patent Application No. WO 94/14780.
PCT Patent Application No. WO 93/13055.
PCT Patent Application No. WO 99/62875.
European Patent No. EP0446699A1.
U.S. Pat. No. 5,132,453.
U.S. Pat. No. 5,684,008.
U.S. Pat. No. 5,830,917.
U.S. Pat. No. 5,854,251.
U.S. Pat. No. 5,863,931.
U.S. Pat. No. 5,919,787.
U.S. Pat. No. 5,945,408.
U.S. Pat. No. 5,981,511.
PCT Patent Application No. WO 95/25717 discloses certain amidino derivatives as being useful in inhibiting inducible nitric oxide synthase.
PCT Patent Application No. WO 99/62875 discloses further amidino compounds as being useful in inhibiting inducible nitric oxide synthase.
Compounds have now been found which have the advantage of being very efficacious as iNOS inhibitors in the human cartilage explant assay, a model for osteoarthritis. At the same time the compounds of the present invention are surprisingly unable to penetrate certain non-target organs in test systems, especially in comparison to the compounds of WO 95/25717. This surprising differentiation in expected access between the target organ (cartilage) and other organs is an unexpected advantage for the compounds of the present invention.
In a broad aspect, the present invention is directed to novel compounds, pharmaceutical compositions and methods of using said compounds and compositions for inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoforms of nitric oxide synthase. It is also another object of the present invention to lower nitric oxide levels in a subject in need of such lowering. The present compounds possess useful nitric oxide synthase inhibiting activity, and are expected to be useful in the treatment or prophylaxis of a disease or condition in which the synthesis or over-synthesis of nitric oxide forms a contributory part.
In one embodiment, the present invention provides a compound or a salt thereof, the compound having a structure corresponding to Formula 1:
wherein:
X is selected from the group consisting of xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, and xe2x80x94S(O)2xe2x80x94;
R2 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C5 alkoxy-C1 alkyl, and C1-C5 alkylthio-C1 alkyl;
with respect to R3 and R8:
R8 is selected from the group consisting of xe2x80x94OR14 and xe2x80x94N(R15)(R16); and R3 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94R17, xe2x80x94C(O)xe2x80x94Oxe2x80x94R18, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R19; or
R8 is xe2x80x94N(R20)xe2x80x94, and R3 is xe2x80x94C(O)xe2x80x94, wherein R8 and R3 together with the atoms to which they are attached form a ring; or
R8 is xe2x80x94Oxe2x80x94, and R3 is xe2x80x94C(R21)(R22)xe2x80x94, wherein R8 and R3 together with the atoms to which they are attached form a ring;
if R3 is xe2x80x94C(R21)(R22)xe2x80x94, then R4 is xe2x80x94C(O)xe2x80x94Oxe2x80x94R23; otherwise R4 is xe2x80x94H;
R1, R5, R6, and R7 independently are selected from the group consisting of xe2x80x94H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl;
R9 and R10 independently are selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl;
with respect to R11 and R12:
R11 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R24, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R25; and R12 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R26, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R27; or
R11 is xe2x80x94Oxe2x80x94, and R12 is xe2x80x94C(O)xe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring; or
R11 is xe2x80x94C(O)xe2x80x94, and R12 is xe2x80x94Oxe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring; and
R13 is C1 alkyl;
R14 is selected from the group consisting of xe2x80x94H and C1-C6 alkyl; wherein when R14 is C1-C6 alkyl, R14 is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
with respect to R15 and R16:
R15 is selected from the group consisting of xe2x80x94H, alkyl, and alkoxy; and R16 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, alkyl, alkoxy, xe2x80x94C(O)xe2x80x94R27a, xe2x80x94C(O)xe2x80x94Oxe2x80x94R28, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R29; wherein when R15 and R16 independently are alkyl or alkoxy, R15 and R16 independently are optionally substituted with one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; or
R15 is xe2x80x94H; and R16 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R27a, R28 , and R29 independently are selected from the group consisting of xe2x80x94H and alkyl, which is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
when any of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25 R26, R27, R27a, R28, and R29 independently is a moiety selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl, then the moiety is optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen.
Another embodiment provides a method for the treatment or prevention of an inflammation-related disorder wherein the method comprises treating a subject in need thereof with an inflammation-related disorder treating or preventing amount of a compound of the present invention.
In yet another embodiment the present invention provides a method for the preparation of a compound of Formula 1, wherein the method comprises treating a diamine compound having a structure corresponding to Formula 22:
or a salt thereof, with an alkyl acetimidate having a structure corresponding to Formula 23:
wherein R31 is C1-C6 alkyl. The treating can, if desired, be performed in the presence of an acid or a base, preferably in the presence of a base.
In a further embodiment of the present invention provides a method for the preparation of a diamine compound having a structure corresponding to Formula 22:
or a salt thereof, wherein R30 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94R17, xe2x80x94C(O)xe2x80x94Oxe2x80x94R18, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R19, and the other substituents are as defined above, wherein the method comprises treating a protected diamine compound having the structure corresponding to Formula 24:
or a salt thereof, wherein R33 is selected from the group consisting of xe2x80x94H and a protected amino group; and R32 is a protected amino group; and R14 is selected from the group consisting of xe2x80x94H and C1-C6 alkyl; wherein when R14 is C1-C6 alkyl, R14 is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the treating is performed with a deprotecting reagent, thereby producing the diamine compound.
Compounds of Formula 1 will be useful for treating, among other things, inflammation in a subject, or for treating other nitric oxide synthase-mediated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the present invention will be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis. Conditions in which the compounds of the present invention will provide an advantage in inhibiting NO production from L-arginine include arthritic conditions.
Compounds of the invention will be further useful in the treatment of asthma, bronchitis, menstrual cramps (e.g., dysmenorrhea), premature labor, tendinitis, bursitis, skin-related conditions such as psoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis, and from post-operative inflammation including from ophthalmic surgery such as cataract surgery and refractive surgery. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis. Compounds of the invention would be useful for the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin. Compounds of the invention would be useful in treating inflammation and tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin""s disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet""s syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The compounds would also be useful in the treatment of ophthalmic diseases, such as glaucoma, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue. Of particular interest among the uses of the present inventive compounds is the treatment of glaucoma, especially where symptoms of glaucoma are caused by the production of nitric oxide, such as in nitric oxide-mediated nerve damage. The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer""s disease, and central nervous system damage resulting from stroke, ischemia and trauma. The compounds of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis. The compounds would also be useful in the treatment of pain, but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer. The compounds would be useful for the prevention of dementias, such as Alzheimer""s disease.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional antiinflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.
Other conditions in which the compounds of the present invention will provide an advantage in inhibiting NO inhibition include cardiovascular ischemia, diabetes (type I or type II), congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (for example, secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson""s disease. Further neurodegenerative disorders in which NO inhibition may be useful include nerve degeneration or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in cases of central nervous system (CNS) trauma (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia e.g. pre-senile dementia, and AIDS-related dementia, cachexia, Sydenham""s chorea, Huntington""s disease, Amyotrophic Lateral Sclerosis, Korsakoffs disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock.
The compounds of the present invention will also be useful in the treatment of pain including somatogenic (either nociceptive or neuropathic), both acute and chronic. A nitric oxide inhibitor could be used in any situation including neuropathic pain that a common NSAID or opioid analgesic would traditionally be administered.
Still other disorders or conditions which will be advantageously treated by the compounds of the present invention include treatment of prevention of opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine addiction, alcoholism, and eating disorders. The compounds and methods of the present invention will also be useful in the treatment or prevention of drug withdrawal symptoms, for example treatment or prevention of symptoms of withdrawal from opiate, alcohol, or tobacco addiction. The present inventive compounds may also be useful to prevent tissue damage when therapeutically combined with antibacterial or antiviral agents.
The compounds of the present invention will also be useful in inhibiting NO production from L-arginine including systemic hypotension associated with septic and/or toxic hemorrhagic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy.
The present invention is further directed to the use of the compounds of the present invention for the treatment and prevention of neoplasias. The neoplasias that will be treatable or preventable by the compounds and methods of the present invention include brain cancer, bone cancer, a leukemia, a lymphoma, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body. Preferably, the neoplasia is selected from gastrointestinal cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers. The present compounds and methods can also be used to treat the fibrosis which occurs with radiation therapy. The present compounds and methods can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, the present compounds and methods can be used to prevent polyps from forming in patients at risk of FAP.
Conjunctive treatment of a compound of the present invention with another antineoplastic agent will produce a synergistic effect or alternatively reduce the toxic side effects associated with chemotherapy by reducing the therapeutic dose of the side effect-causing agent needed for therapeutic efficacy or by directly reducing symptoms of toxic side effects caused by the side effect-causing agent. A compound of the present invention will further be useful as an adjunct to radiation therapy to reduce side effects or enhance efficacy. In the present invention, another agent which can be combined therapeutically with a compound of the present invention includes any therapeutic agent which is capable of inhibiting the enzyme cyclooxygenase-2 (xe2x80x9cCOX-2xe2x80x9d). Preferably such COX-2 inhibiting agents inhibit COX-2 selectively relative to the enzyme cyclooxygenase-1(xe2x80x9cCOX-1xe2x80x9d). Such a COX-2 inhibitor is known as a xe2x80x9cCOX-2 selective inhibitorxe2x80x9d. More preferably, a compound of the present invention can be therapeutically combined with a COX-2 selective inhibitor wherein the COX-2 selective inhibitor selectively inhibits COX-2 at a ratio of at least 10:1 relative to inhibition of COX-1, more preferably at least 30:1, and still more preferably at least 50:1 in an in vitro test. COX-2 selective inhibitors useful in therapeutic combination with the compounds of the present invention include celecoxib, valdecoxib, deracoxib, etoricoxib, rofecoxib, ABT-963 (2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl) phenyl-3(2H)-pyridazinone; described in PCT Patent Application No. WO 00/24719), or meloxicam. A compound of the present invention can also be advantageously used in therapeutic combination with a prodrug of a COX-2 selective inhibitor, for example parecoxib.
Another chemotherapeutic agent which will be useful in combination with a compound of the present invention can be selected, for example, from the following non-comprehensive and non-limiting list:
Alpha-difluoromethylornithine (DFMO), 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck and Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2xe2x80x2-furanidyl)-5-fluorouracil, Daiichi Seiyaku OF-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SKandF-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin, trimelamol, Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 zorubicin, alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY40481, Vestar boron-1O, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemex CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP49532, Rhone-Poulenc RP-56976, SmithKline SKandF-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides, Yamanouchi YM-534, uroguanylin, combretastatin, dolastatin, idarubicin, epirubicin, estramustine, cyclophosphamide, 9-amino-2-(S)-camptothecin, topotecan, irinotecan (Camptosar), exemestane, decapeptyl (tryptorelin), or an omega-3 fatty acid.
Examples of radioprotective agents which may be used in a combination therapy with the compounds of this invention include AD-5, adchnon, amifostine analogues, detox, dimesna, 1-102, MM-159, N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.
The compounds of the present invention will also be useful in treatment or prevention of angiogenesis-related disorders or conditions, for example, tumor growth, metastasis, macular degeneration, and atherosclerosis.
In a further embodiment, the present invention also provides therapeutic combinations for the treatment or prevention of ophthalmic disorders or conditions such as glaucoma. For example the present inventive compounds advantageously will be used in therapeutic combination with a drug which reduces the intraocular pressure of patients afflicted with glaucoma. Such intraocular pressure-reducing drugs include without limitation latanoprost, travoprost, bimatoprost, or unoprostol. The therapeutic combination of a compound of the present invention plus an intraocular pressure-reducing drug will be useful because each is believed to achieve its effects by affecting a different mechanism.
In another combination of the present invention, the present inventive compounds can be used in therapeutic combination with an antihyperlipidemic or cholesterol-lowering drug such as a benzothiepine or a benzothiazepine antihyperlipidemic drug. Examples of benzothiepine antihyperlipidemic drugs useful in the present inventive therapeutic combination can be found in U.S. Pat. No. 5,994,391, herein incorporated by reference. Some benzothiazepine antihyperlipidemic drugs are described in WO 93/16055. Alternatively, the antihyperlipidemic or cholesterol-lowering drug useful in combination with a compound of the present invention can be an HMG Co-A reductase inhibitor. Examples of HMG Co-A reductase inhibitors useful in the present therapeutic combination include, individually, benfluorex, fluvastatin, lovastatin, provastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, ZD-9720 (described in PCT Patent Application No. WO 97/06802), ZD-4522 (CAS No. 147098-20-2 for the calcium salt; CAS No. 147098-18-8 for the sodium salt; described in European Patent No. EP 521471), BMS 180431 (CAS No. 129829-03-4), or NK-104 (CAS No. 141750-63-2). The therapeutic combination of a compound of the present invention plus an antihyperlipidemic or cholesterol-lowering drug will be useful, for example, in reducing the risk of formation of atherosclerotic lesions in blood vessels. For example, atherosclerotic lesions often initiate at inflamed sites in blood vessels. It is established that antihyperlipidemic or cholesterol-lowering drug reduce risk of formation of atherosclerotic lesions by lowering lipid levels in blood. Without limiting the invention to a single mechanism of action, it is believed that one way the compounds of the present combination will work in concert to provide improved control of atherosclerotic lesions by, for example, reducing inflammation of the blood vessels in concert with lowering blood lipid levels.
In another embodiment of the invention, the present compounds can be used in combination with other compounds or therapies for the treatment of central nervous conditions or disorders such as migraine. For example, the present compounds can be used in therapeutic combination with caffeine, a 5xe2x80x94HT-1B/1D agonist (for example, a triptan such as sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, or frovatriptan), a dopamine D4 antagonist (e.g., sonepiprazole), aspirin, acetaminophen, ibuprofen, indomethacin, naproxen sodium, isometheptene, dichloralphenazone, butalbital, an ergot alkaloid (e.g., ergotamine, dihydroergotamine, bromocriptine, ergonovine, or methyl ergonovine), a tricyclic antidepressant (e.g., amitriptyline or nortriptyline), a serotonergic antagonist (e.g., methysergide or cyproheptadine), a beta-andrenergic antagonist (e.g., propranolol, timolol, atenolol, nadolol, or metprolol), or a monoamine oxidase inhbitor (e.g., phenelzine or isocarboxazid).
A further embodiment provides a therapeutic combination of a compound of the present invention with an opioid compound. Opioid compounds useful in this combination include without limitation morphine, methadone, hydromorphone, oxymorphone, levorphanol, levallorphan, codeine, dihydrocodeine, dihydrohydroxycodeinone, pentazocine, hydrocodone, oxycodone, nalmefene, etorphine, levorphanol, fentanyl, sufentanil, DAMGO, butorphanol, buprenorphine, naloxone, naltrexone, CTOP, diprenorphine, beta-funaltrexamine, naloxonazine, nalorphine, pentazocine, nalbuphine, naloxone benzoylhydrazone, bremazocine, ethylketocyclazocine, U50,488, U69,593, spiradoline, nor-binaltorphimine, naltrindole, DPDPE, [D-la2, glu4]deltorphin, DSLET, met-enkephalin, leu-enkaphalin, beta-endorphin, dynorphin A, dynorphin B, and alpha-neoendorphin. An advantage to the combination of the present invention with an opioid compound is that the present inventive compounds will allow a reduction in the dose of the opioid compound, thereby reducing the risk or severity of opioid side effects, such as opioid addiction.
The term xe2x80x9calkylxe2x80x9d, alone or in combination, means an acyclic alkyl radical, linear or branched, preferably containing from 1 to about 10 carbon atoms and more preferably containing from 1 to about 6 carbon atoms. xe2x80x9cAlkylxe2x80x9d also encompasses cyclic alkyl radicals containing from 3 to about 7 carbon atoms, preferably from 3 to 5 carbon atoms. Said alkyl radicals can be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond. Such radicals containing from 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, more preferably from 2 to about 3 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
The term xe2x80x9calkynylxe2x80x9d refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds, such radicals containing 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, more preferably from 2 to about 3 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term xe2x80x9calkoxyxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of 1 to about 6 carbon atoms, preferably 1 to about 3 carbon atoms, such as a methoxy radical. The term xe2x80x9calkoxyalkylxe2x80x9d also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy alkyls. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of 1 to about 6 carbon atoms, attached to a divalent sulfur atom. An example of xe2x80x9clower alkylthioxe2x80x9d is methylthio (CH3xe2x80x94Sxe2x80x94).
The term xe2x80x9calkylthioalkylxe2x80x9d embraces alkylthio radicals, attached to an alkyl group. Examples of such radicals include methylthiomethyl.
The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term xe2x80x9cheterocyclylxe2x80x9d means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms is replaced by N, S, P, or O. This includes, for example, the following structures: 
wherein Z, Z1, Z2 or Z3 is C, S, P, O, or N, with the proviso that one of Z, Z1, Z2 or Z3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z1, Z2 or Z3 only when each is C. The term xe2x80x9cheterocyclylxe2x80x9d also includes fully saturated ring structures such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. The term xe2x80x9cheterocyclylxe2x80x9d also includes partially unsaturated ring structures such as dihydrofuranyl, pyrazolinyl, imidazolinyl, pyrrolinyl, chromanyl, dihydrothiophenyl, and others.
The term xe2x80x9cheteroarylxe2x80x9d means a fully unsaturated heterocycle.
In either xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheteroaryl,xe2x80x9d the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
The term xe2x80x9ccycloalkylxe2x80x9d means a mono- or multi-ringed carbocycle wherein each ring contains three to about seven carbon atoms, preferably three to about five carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term xe2x80x9ccycloalkylxe2x80x9d additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring of the benzothiepine.
The term xe2x80x9coxoxe2x80x9d means a doubly bonded oxygen.
The term xe2x80x9calkoxyxe2x80x9d means a radical comprising an alkyl radical that is bonded to an oxygen atom, such as a methoxy radical. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to about ten carbon atoms. Still more preferred alkoxy radicals have one to about six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
The term xe2x80x9carylxe2x80x9d means a fully unsaturated mono- or multi-ring carbocycle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.
The term xe2x80x9cCombination therapyxe2x80x9d means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure, for example atherosclerosis, pain, inflammation, migraine, neoplasia, angiogenisis-related condition or disorder, or other. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
The phrase xe2x80x9ctherapeutically effectivexe2x80x9d is intended to qualify the combined amount of active ingredients in the combination therapy. This combined amount will achieve the goal of reducing or eliminating the hyperlipidemic condition.
In one embodiment, the present invention provides a compound or a salt thereof, the compound having a structure corresponding to Formula 1:
In the structure of Formula 1, X is selected from the group consisting of xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, and xe2x80x94S(O)2xe2x80x94. Preferably, X is xe2x80x94Sxe2x80x94. R2 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C5 alkoxy-C1 alkyl, and C1-C5 alkylthio-C1 alkyl wherein each of these groups is optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen. Preferably, R2 is C1-C6 alkyl optionally substituted with a substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen. With respect to R3 and R8, R8 is selected from the group consisting of xe2x80x94OR14 and xe2x80x94N (R15)(R16), and R3 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94R17, xe2x80x94C(O)xe2x80x94Oxe2x80x94R18, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R19; or RS is xe2x80x94N(R20)xe2x80x94, and R3 is xe2x80x94C(O)xe2x80x94, wherein R8 and R3 together with the atoms to which they are attached form a ring; or R8 is xe2x80x94Oxe2x80x94, and R3 is xe2x80x94C(21)(R)xe2x80x94, wherein R8 and R3 together with the atoms to which they are attached form a ring. If R3 is xe2x80x94C(R2) (R22)xe2x80x94, then R4 is xe2x80x94C(O)xe2x80x94Oxe2x80x94R23; otherwise R4 is xe2x80x94H. R1, R5, R6, and R7 independently are selected from the group consisting of xe2x80x94H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl. R9 and R10 independently are selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl. With respect to R11 and R12, R11 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R24, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R25, and R12 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R27; or R11 is xe2x80x94Oxe2x80x94, and R12 is xe2x80x94C(O)xe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring; or R11 is xe2x80x94C(O)xe2x80x94, and R12 is xe2x80x94Oxe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring. R13 is C1 alkyl. R14 is selected from the group consisting of xe2x80x94H and C1-C6 alkyl, wherein when R14 is C1-C6 alkyl, R14 is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. With respect to R15 and R16, R15 is selected from the group consisting of xe2x80x94H, alkyl, and alkoxy, and R16 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, alkyl, alkoxy, xe2x80x94C(O)xe2x80x94R27a, xe2x80x94C(O)xe2x80x94Oxe2x80x94R28, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R29; wherein when R15 and R16 independently are alkyl or alkoxy, R15 and R16 independently are optionally substituted with one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; or R15 is xe2x80x94H; and R16 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R27a, R28, and R29 independently are selected from the group consisting of xe2x80x94H and alkyl, wherein alkyl is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. When any of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R27a, R28, and R29 independently is a moiety selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl, then the moiety is optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen.
In a preferred embodiment, R8 is xe2x80x94OH. When R8 is xe2x80x94OH, preferably X is S. In a further embodiment, R1, R5, R6, R7, R9, and R10 independently are selected from the group consisting of xe2x80x94H and C1-C3 alkyl. Preferably R5, R6, R7, R9, R10 each are xe2x80x94H. R13 can be a variety of groups, for example fluoromethyl or methyl. R1 can be C1-C6 alkyl optionally substituted with a substituent selected from the group consisting of xe2x80x94OH and halogen; preferably R1 is C1 alkyl optionally substituted with halogen; more preferably R1 is selected from the group consisting of fluoromethyl, hydroxymethyl, and methyl. In one important embodiment R1 can be methyl. Alternatively, R1 can be fluoromethyl. In another alternative R1 can be hydroxymethyl. In another embodiment, R2 is C1-C6 alkyl optionally substituted with a substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen. In one preferred embodiment R2 is C1 alkyl optionally substituted with halogen. For example, R2 can be methyl. Alternatively, R2 can be fluoromethyl. In yet another example, R2 can be hydroxymethyl. In still another example, R2 can be methoxymethyl.
In the compounds of the present invention, it is preferred that R3, R4, R11 and R12 each is xe2x80x94H. In this embodiment, it is further preferred that R1, R5, R6, R7, R9, and R10 independently are selected from the group consisting of xe2x80x94H and C1-C3 alkyl. Preferably R5, R6, R7, R9, R10 each is xe2x80x94H. In this further embodiment, R13 can be, for example, fluoromethyl, or in another example R13 can be methyl. In preferred compounds of these examples, R2 is C1-C6 alkyl optionally substituted with a substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen. Preferably R2 is C1 alkyl optionally substituted with halogen. In one such example R2 is fluoromethyl. In another example R2 is methyl. Alternatively R2 can be hydroxymethyl. In another alternative, R2 can be methoxymethyl.
When R13 is methyl, R1 can be, for example, xe2x80x94H or C1-C6 alkyl optionally substituted with a substituent selected from the group consisting of xe2x80x94OH and halogen. In a preferred embodiment R1 is xe2x80x94H. Alternatively, R1 can be C1-C6 alkyl optionally substituted with a substituent selected from the group consisting of xe2x80x94OH and halogen. For example R1 can be methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, isobutyl, t-butyl, a pentyl isomer, or a hexyl isomer. For example, R1 can be ethyl. Alternatively, R1 can be C1 alkyl optionally substituted with a substituent selected from the group consisting of xe2x80x94OH and halogen; for example R1 can be methyl. Alternatively, R1 can be fluoromethyl. In another alternative, R1 can be hydroxymethyl.
In another embodiment R8 can be xe2x80x94OR14. R14 can be as defined above. Preferably R14 is C1-C6 alkyl optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; more preferably R14 is C1-C3 alkyl; and more preferably still R14 is methyl. In yet another embodiment of compound 1, R8 can be xe2x80x94N(R15)(R16), wherein R15 and R16 are as defined above. In still another embodiment R8 can be xe2x80x94N(R)xe2x80x94, and R3 can be xe2x80x94C(O)xe2x80x94, wherein R8 and R3 together with the atoms to which they are attached form a ring. In another embodiment still, R8 can be xe2x80x94Oxe2x80x94, and R3 can be xe2x80x94C(R21)(R22)xe2x80x94, wherein R8 and R3 together with the atoms to which they are attached form a ring.
In the compound of Formula 1, R11 can be selected from the group consisting of xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R24, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R25. Preferably R11 is xe2x80x94OH. In a further embodiment R12 is xe2x80x94H when R11 is xe2x80x94OH.
However, the present invention also provides useful compounds of Formula 1 in which R11 is xe2x80x94Oxe2x80x94, and R12 is xe2x80x94C(O)xe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring. In another useful embodiment R11 is xe2x80x94C(O)xe2x80x94, and R12 is xe2x80x94Oxe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring. Alternatively, R12 can be selected from the group consisting of xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R, and xe2x80x94C (O)xe2x80x94Sxe2x80x94R27. In this alternative, R11 is preferably xe2x80x94H.
The present invention also provides pharmaceutically-acceptable salts of the compounds of Formula 1. For example, such a pharmaceutically acceptable salt can be one in which the present inventive compound is in a cationic form with at least one anionic counterion. Examples of anionic counterions useful in the pharmaceutically-acceptable salts of the present invention include a halide, a carboxylate, a sulfonate, a sulfate, a phosphate, a phosphonate, a resin-bound anion, or a nitrate. When the anionic counterion is a halide, it can be, for example fluoride, chloride, bromide, or iodide. Preferably the halide counterion is chloride. When the anionic counterion is a carboxylate (i.e., the anionic form of a compound containing a carboxylic acid functional group), the carboxylate counterion can vary widely. The carboxylate counterion can be, for example, formate, acetate, propionate, trifluoroacetate, succinate, salicylate, DL-aspartate, D-aspartate, L-aspartate, DL-glutamate, D-glutamate, L-glutamate, glycerate, succinate, steric, DL-taarate, D-tartarate, L-tarrate, (xc2x1)-mandelate, (R)-(xe2x88x92)-mandelate, (S)-(+)-mandelate, citrate, mucate, maleate, malonate, benzoate, DL-malate, D-malate, L-malate, hemi-malate, 1-adamantaneacetate, 1-adamantanecarboxylate, flavianate, sulfonoacetate, (A)-lactate, L-(+)-lactate, D-(xe2x88x92)-lactate, pamoate, D-alpha-galacturonate, glycerate, DL-ascorbate, D-ascorbate, L-ascorbate, DL-cystate, D-cystate, L-cystate, DL-homocystate, D-homocystate, L-homocystate, DL-cysteate, D-cysteate, L-cysteate, (4S)-hydroxy-L-proline, cyclopropane-1,1-dicarboxylate, 2,2-dimethylmalonate, squarate, tyrosine anion, proline anion, fumarate, 1-hydroxy-2-naphthoate, phosphonoacetate, carbonate, bicarbonate, 3-phosphonopropionate, DL-pyroglutamate, D-pyroglutamate, or L-pyroglutamate. Alternatively, the anionic counterion can be a sulfonate. For example the sulfonate counterion can be methanesulfonate, toluenesulfonate, benzenesulfonate, trifluoromethylsulfonate, ethanesulfonate, (xc2x1)-camphorsulfonate, naphthalenesulfonate, 1R-(xe2x88x92)-camphorsulfonate, 1S-(+)-camphorsulfonate, 2-mesitylenesulfonate, 1,5-naphthalenedisulfonate, 1,2-ethanedisulfonate, 1,3-propanedisulfonate, 3-(N-morpholino)propane sulfonate, biphenylsulfonate, isethionate, or 1-hydroxy-2-naphthalenesulfonate. In another embodiment the anionic counterion can be a sulfate. Examples of sulfates useful in the present invention include without limitation sulfate, monopotassium sulfate, monosodium sulfate, and hydrogen sulfate. The anionic counterion can be a sulfamate. When the anionic counterion is a phosphate, it can be, for example, phosphate, dihydrogen phosphate, potassium hydrogen phosphate, dipotassium phosphate, potassium phosphate, sodium hydrogen phosphate, disodium phosphate, sodium phosphate, calcium dihydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, calcium phosphate tribasic, or hexafluorophosphate. The anionic counterion can be a phosphonate. For example, the phosphonate counterion can be vinylphosphonate, 2-carboxyethylphosphonate or phenylphosphonate. Alternatively, the anionic counterion can be nitrate. The salt can also result from the addition of the compound with an oxide such as zinc oxide.
The anionic counterion can, if desired, be bound to a polymeric resin. In other words, the anionic counterion can be a resin-bound anion. For example the resin-bound anion can be a polyacrylate resin wherein the resin contains anionic carboxylate groups. An example of a polyacrylate resin useful in the salts of the present invention is Bio-Rex 70 (produced by Bio-Rad). In an alternative example, the resin-bound anion can be a sulfonated poly (styrene divinylbenzene) copolymer resin. Non-limiting examples of sulfonated poly (styrene divinylbenzene) copolymer resins useful as anionic counterions in the present invention include Amberlite IPR-69 (Rohm and Haas) or Dowex 50WX4-400 (Dow). The polyacrylate resin or the sulfonated poly(styrene divinylbenzene) resin can be, if desired, crosslinked with a crosslinking agent such as divinylbenzene.
In another embodiment, the pharmaceutically acceptable salt of the compound of Formula 1 can be one in which the present inventive compound is in an anionic form with at least one cationic counterion. The cationic counterion can be, for example, an ammonium cation, a alkali metal cation, an alkaline earth metal cation, a transition metal cation, or a resin-bound cation. When the cationic counterion is an ammonium cation, it can be substituted or unsubstituted. For example, the ammonium cation can be an alkylammonium cation or a di-, tri-, or tetra-alkylammonium cation. Alternatively the ammonium cation can be an arylammonium or a di-, tri-, or tetra-arylammonium cation. The ammonium cation can contain both alkyl and aryl groups. The ammonium cation can be aromatic, for example a pyridinium cation. Other functional groups can also be present in the ammonium cation. The ammonium cation can be, for example, ammonium, methyl ammonium, dimethylammonium, trimethylammonium, tetramethylammonium, ethanolammonium, dicyclohexylammonium, guanidinium, or ethylenediammonium cation. Alternatively the cationic counterion can be an alkali metal cation such as lithium cation, sodium cation, potassium cation or cesium cation. In another alternative the cationic counterion can be an alkaline earth metal cation such as beryllium cation, magnesium cation, or calcium cation. The cation, if preferred, can be a transition metal cation such as zinc cation.
The cationic counterion can, if desired, be bound to a polymeric resin. In other words, the anionic counterion can be a resin-bound cation. For example, the resin-bound cation can be a cationically functionalized poly(styrene divinylbenzene) resin. An example of a cationically functionalized poly(styrene divinylbenzene) resin useful in the present invention is Bio-Rex-5 (Bio-Rad), an ammonium-functionalized resin. In another alternative, the resin-bound cation can be a cationically functionalized polyacrylic resin such as an aminated polyacrylic resin. An example of an aminated polyacrylic resin useful as the cationic counterion of the present invention is AG4-XR (Bio-Rad).
In yet another embodiment of the present invention the compound of Formula 1 can be present in a zwitterionic form. In other words, the compound can contain both cationic and anionic sites within the molecule. Such a zwitterionic form can exist without a separate counterion or it can exist with both a cationic counterion and an anionic counterion.
Another embodiment provides a method for the treatment or prevention of an inflammation-related disorder wherein the method comprises treating a subject in need thereof with an inflammation-related disorder-treating or preventing amount of a compound or salt of the present invention.
In yet another embodiment the present invention provides a method for the preparation of a compound of Formula 21:
or a salt thereof, wherein: X is selected from the group consisting of xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, and xe2x80x94S(O)2xe2x80x94; R2 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C5 alkoxy-C1 alkyl, and C1-C5 alkylthio-C1 alkyl; R30 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, C(O)xe2x80x94R17, xe2x80x94C(O)xe2x80x94Oxe2x80x94R18, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R19; R1, R5, R6, and R7 independently are selected from the group consisting of xe2x80x94H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl; R9 and R10 independently are selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl; with respect to R11 and R12:
R11 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R24, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R25; and R12 is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94C(O)xe2x80x94Oxe2x80x94R26, and xe2x80x94C(O)xe2x80x94Sxe2x80x94R27; or R11 is xe2x80x94Oxe2x80x94, and R12 is xe2x80x94C(O)xe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring; or R11 is xe2x80x94C(O)xe2x80x94, and R12 is xe2x80x94Oxe2x80x94, wherein R11 and R12 together with the atoms to which they are attached form a ring;
R13 is C1 alkyl;
R17, R18, R19, R24, R25, R26, R27, and R27a independently are selected from the group consisting of xe2x80x94H and alkyl, which is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; and when any of R1, R2, R4, R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R24, R25 R26, R27, and R27a independently is a moiety selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl, then the moiety is optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen. The present method of preparing compound 21 comprises treating a diamine compound having a structure corresponding to Formula 22:
(or a salt thereof) with an alkyl acetimidate having a structure corresponding to Formula 23:
(or a salt thereof) wherein R31 is C1-C6 alkyl. Preferably R11 is selected from the group consisting of xe2x80x94H and xe2x80x94OH. R11 can, for example be xe2x80x94H. Alternatively, R11 can be xe2x80x94OH. When R11 is xe2x80x94H or xe2x80x94OH, preferably R13 is methyl or halomethyl. More preferably R13 is methyl. Also when R11 is xe2x80x94H or xe2x80x94OH, preferably R31 is C1-C3 alkyl, and more preferably ethyl. In a preferred embodiment, the treating of the diamine compound with the alkyl acetimidate is performed in the presence of a base. For example, the base can be a hydrazine, a metal sulfide, a metal hydroxide, a metal alkoxide, an amine, a hydroxylamine, a metal hydride, a metal amide complex, or a basic resin. When the base is a basic resin it can be, for example a polymer-bound diazabicyclo[4.4.0]dec-2-ene resin. For example, the basic resin can have a poly(styrene divinylbenzene) copolymer backbone with diazabicyclo[4.4.0]dec-2-ene bonded to the copolymer. When the base is an amine, it can be essentially any substituted or unsubstituted amine. For example, the amine can be 1,5-diazabicyclo[4.3.0]non-5-ene; 1,4-diazabicyclo [2.2.2]octane; or 1,8-diazabicyclo[5.4.0]undec-7-ene. When the base is an alkali metal hydroxide it can be, for example, potassium hydroxide or sodium hydroxide. When the base is a metal hydride it can be, for example, sodium hydride, potassium hydride, or calcium hydride.
In a further embodiment of the present invention provides a method for the preparation of a diamine compound having a structure corresponding to Formula 22 (or a salt thereof), wherein the method comprises treating a protected diamine compound having the structure corresponding to Formula 24:
(or a salt thereof) wherein R33 is selected from the group consisting of xe2x80x94NH2 and a protected amino group; and R32 is a protected amino group; and R14 is selected from the group consisting of xe2x80x94H and C1-C6 alkyl; wherein when R14 is C1-C6 alkyl, R14 is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the treating is performed with a deprotecting reagent, thereby producing the diamine compound. Protected amino groups useful in the present invention vary widely in nature. Numerous protected amino groups useful in the present invention for either R32 or R33 are described by Theodora W. Greene and Peter G. M. Wuts (Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons, New York, 1999, pp. 494-653). For example either or both of R32 and R33 can be a 4-chlorobenzylimino group. When R33 is a 4-chlorobenzylimino group, preferably R32 is xe2x80x94NH2. In another embodiment, either or both of R32 and R33 can be a t-butoxycarbonylamino group. When R33 is a t-butoxycarbonylamino group, preferably R32 is xe2x80x94NH2. In yet another embodiment, either or both of R32 and R33 can be an N-phthalimido group. When R33 is an N-phthalimido group, preferably R32 is xe2x80x94NH2. In another embodiment, either or both of R32 and R33 can be a benzyloxycarbonylamino group. In one preferred embodiment of the present invention, the protected amino group is any such group resulting from the reaction of an aldehyde with the corresponding amino group to form a Schiff base. A large variety of deprotecting reagents can be advantageously used in the present invention to effect the conversion of 24 to 22. Many such deprotecting reagents are described by Greene and Wuts, supra. For example, when the protected amino group is a 4-chlorobenzylimino group or a t-butoxycarbonylamino group, preferably the deprotecting reagent is an acid. Some useful acid deprotecting agents include without limitation hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, phosphoric acid, phosphorus acid, and acetic acid. In another example, when R32 or R33 is an N-phthalimido group, the deprotecting reagent can be either an acid or a base. When the deprotecting reagent for the N-phthalimido group is a base, the base can be, for example, a hydrazine, a metal sulfide, a metal hydroxide, a metal alkoxide, an amine, a hydroxylamine, and a metal amide complex. When the deprotecting reagent for the N-phthalimido group is an acid, the acid can be, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, phosphorus acid, or acetic acid. Preferably the treating of compound 24 with the deprotecting reagent is performed in the presence of water.
In the present reaction, R14 is preferably xe2x80x94H. R33 preferably is xe2x80x94NH2, or a salt thereof R2 is preferably methyl. In another preferred embodiment R1, R5, R6, R7, R9, and R10 each is xe2x80x94H. A further preferred embodiment is one in which R33 is a t-butoxycarbonylamino group. In a particularly preferred embodiment, compound 24 has the structure corresponding to Formula 25:
(or a salt thereof) wherein the parenthetical R means that the carbon alpha to the carboxylic acid function is in the R absolute configuration. In other words, compound 25 is the R-enantiomer or a salt thereof.
The present invention also provides a method for the preparation of the protected diamine compound 24 (or a salt thereof) wherein the method comprises treating a sulfhydryl compound having the structure of Formula 26:
with a protected amino ethyl alkylating compound having the structure of Formula 27:
wherein R34 is a nucleophilic substitution leaving group; thereby forming the protected diamine compound. Preferably, this reaction is performed in the presence of a base. The base can be, for example, a hydrazine, a metal sulfide, a metal hydroxide, a metal alkoxide, an amine, a hydroxylamine, and a metal amide complex. Preferably the base is an alkali metal hydroxide and more preferably the base is potassium hydroxide or sodium hydroxide. R34 in the structure of Formula 27 can vary widely and can represent essentially any nucleophilic leaving group which produces either a pharmaceutically acceptable anion or an anion which can be exchanged for a pharmaceutically acceptable anion. In other words, (R34)xe2x88x92 is a pharmaceutically acceptable anion or an anion which can be exchanged for a pharmaceutically acceptable anion. For example, R34 can be chloro, bromo, iodo, methanesulfonato, toluenesulfonato, benzenesulfonato, or trifluoromethanesulfonato. Preferably R34 is chloro, bromo, or iodo and more preferably R34 is bromo. In the present reaction it is preferred for R33 to be xe2x80x94NH2. In the present reaction R2 can be C1-C6 alkyl optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy and halogen. Preferably R2 is C1-C3 alkyl optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy and halogen, and more preferably R2 is C1-C3 alkyl. For example, R2 advantageously can be methyl. In a further embodiment R5 and R6 each can be xe2x80x94H. In yet another embodiment R1 and R7 independently can be selected from the group consisting of H and C1-C6 alkyl optionally substituted by one or more halogen; preferably R1 and R7 each is xe2x80x94H. In the present reaction, R32 preferably can be selected from the group consisting of a 4-chlorobenzylimino group, a t-butoxycarbonylamino group, and an N-phthalimido group, and more preferably R32 is a t-butoxycarbonylamino group.
The present invention also provides a method for the preparation of a sulfhydryl compound having the structure of Formula 28:
wherein R2, R5, and R6 are as defined above, and wherein the method comprises treating under hydrolysis conditions a thiazolidine compound having the structure of Formula 29:
or a salt thereof, wherein R35 is a moiety selected from the group consisting of xe2x80x94H and C 1-C6 alkyl; thereby forming the sulfhydryl compound. The hydrolysis conditions preferably comprise contacting the thiazolidine compound with an acid in the presence of water. Preferably the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, phosphorus acid, and acetic acid. In one embodiment of the present reaction R5 and R6 each is xe2x80x94H. In another embodiment R2 of compound 29 is C1-C6 alkyl optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen. Preferably R2 is C1-C3 alkyl optionally substituted by one or more substituent selected from the group consisting of alkoxy and halogen, and more preferably R2 is C1-C3 alkyl. For example, R2 can be methyl. In another embodiment of the present invention R35 of compound 29 is methyl.
The present invention also provides a method for the preparation of a methyl thiazolidine compound having the structure of Formula 30:
(or a pharmaceutically-acceptable salt thereof wherein R36 is C1-C6 alkyl; wherein the method comprises treating under methylation conditions a deprotonatable thiazolidine compound having the structure of Formula 31:
thereby forming the methyl thiazolidine compound. Preferably the methylation conditions comprise treating the deprotonatable thiazolidine compound with a base and a methylating agent. The nature of the base can vary widely. The base can be, for example, a metal hydroxide, a metal alkoxide, a metal hydride, a metal alkyl, and a metal amide complex. Preferably the base is a metal amide complex. Some metal amide complexes useful as a base in the present invention include without limitation lithium hexamnethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropyl amide, sodium diisopropyl amide, potassium diisopropyl amide, sodium amide, lithium amide, potassium amide, sodium diethylamide, lithium diethylamide, potassium diethylamide, methyl lithium, t-butyl lithium, sec-butyl lithium, methyl sodium, t-butyl sodium, sec-butyl sodium, and methyl magnesium bromide. In the present methylation reaction R36 can be C1-C3 alkyl; for example R36 can be methyl.
The present invention further provides a method for the preparation of the deprotonatable thiazolidine compound 31 wherein the method comprises contacting under condensing conditions a cysteine C1-C6 alkyl ester with pivalaldehyde, thereby forming the deprotonatable thiazolidine compound. Preferably condensing conditions comprise performing the contacting in the presence of a base. The base can vary widely. For example the base can be, without limitation, a hydrazine, a metal sulfide, a metal hydroxide, a metal alkyl base, a metal alkoxide, an amine, a hydroxylamine, and a metal amide complex. When the base is a metal amide complex, it can be, for example, lithium bis(trimethylsilyl)amide. In the present condensation reaction it is preferred that R36 is C1-C3 alkyl, and more preferably R36 is methyl.
In another embodiment the present invention provides a method for the preparation of an alpha-amino acid compound having the structure of Formula 32:
(or a salt, an enantiomer, or a racemate thereof) wherein: R2 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C5 alkoxy-C1 alkyl, and C1-C5 alkylthio-C1 alkyl; R1, R5, R6, and R7 independently are selected from the group consisting of xe2x80x94H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl; R9 and R10 independently are selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl; and when any of R1, R2, R5, R6, R7, R9, and R10 independently is a moiety selected from the group consisting of alky, alkenyl, and alkynyl, then the moiety is optionally substituted by one or more substituent selected from the group consisting of xe2x80x94OH, alkoxy, and halogen; wherein the method comprises treating under hydrolyzing conditions a hydantoin compound having the structure of Formula 33:
(or a salt, an enantiomer, or a racemate thereof), thereby forming the alpha-amino acid compound. The hydrolyzing conditions can comprise, for example, contacting the hydantoin compound with an acid to produce an acid hydrolyzate. Acids useful in the present hydrolysis reaction include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, trifluoroacetic acid, or phosphoric acid. The method for the preparation of alpha-amino acid compound 32 can further comprise treating the acid hydrolyzate with an ion exchange resin. Alternatively, the hydrolyzing conditions can comprise contacting the hydantoin compound with a base to produce a base hydrolyzate. Bases useful in the present base hydrolysis include without limitation a hydrazine, a metal sulfide, a metal hydroxide, or a metal alkoxide. Whether the hydrolysis is base-mediated or acid-mediated, it is preferred that R1, R5, R6, and R7 each is xe2x80x94H in the structure of compound 33. It is also preferred that R9 and R10 each is xe2x80x94H. In a particularly preferred embodiment, the alpha-amino acid compound has the structure of Formula 34:
(or a salt, an enantiomer, or a racemate thereof).
The present invention further provides a method for the preparation of a hydantoin compound having the structure of Formula 35:
(or a salt, an enantiomer, or a racemate thereof) wherein R1, R2, R5, R6, R7, R9, and R10 are as defined above, wherein the method comprises contacting an alpha-sulfo ketone compound having the structure of Formula 36:
with a source of cyanide in the presence of a source of ammonium carbonate and water, thereby producing the hydantoin compound. The source of cyanide can be, for example, hydrogen cyanide or a metal cyanide salt. When the source of cyanide is a metal cyanide salt, preferably the salt is sodium cyanide, potassium cyanide, or lithium cyanide. More preferably the metal cyanide salt is sodium cyanide. For compound 36 in the present hydantoin-forming reaction, R1, R5, R6, and R7 each is preferably xe2x80x94H. It is further preferred that R9 and R10 each is xe2x80x94H. The method of preparing compound 35 can further comprise a chiral separation step. When the method of preparing compound 35 further comprises a chiral separation step, then the hydantoin compound product preferably has the structure of compound 33 (or a salt or an enantiomer thereof).
Also provided by the present invention is a method for the preparation of an alpha-sulfo ketone compound 36 wherein the method comprises contacting an aminothiol compound having the structure of Formula 37:
with di-t-butyl carbonate in the presence of a base to produce an intermediate mixture; and contacting the intermediate mixture with an alpha-chloro ketone compound having the structure of Formula 38:
thereby producing the alpha-sulfo ketone compound. In the present reaction the base can vary widely. For example, the base can be without limitation a hydrazine, a metal sulfide, a metal hydroxide, a metal alkoxide, an amine, a hydroxylamine, and a metal amide complex. Preferably the base is a metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. In the present reaction it is preferred that R1, R5, R6, and R7 each is xe2x80x94H. It is further preferred that R9 and R10 each is xe2x80x94H.
The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to a corresponding parent or neutral compound. Such salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically-acceptable acid addition salts of compounds of the present invention may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids include from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic (including carbonate and hydrogen carbonate anions), sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts. All of these salts may be prepared by conventional means from the corresponding conjugate base or conjugate acid of the compounds of the present invention by reacting, respectively, the appropriate acid or base with the conjugate base or conjugate acid of the compound. Another pharmaceutically acceptable salt is a resin-bound salt.
While it may be possible for the compounds of the present invention to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of The present invention or a pharmaceutically acceptable salt or solvate thereof with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The compounds of Formula 1 are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
The terms xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have two highest ranking groups on the same side of the double bond (xe2x80x9ccisxe2x80x9d) or on opposite sides of the double bond (xe2x80x9ctransxe2x80x9d). Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d geometric forms.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
The following general synthetic sequences are useful in making the present invention. 
The following structures are illustrative of the many compounds provided by the present invention. The examples provided here are not intended to be limiting and one of skill in the art, given the present disclosure, will recognize that many alternative structures are embraced by the present invention. 
The following compounds are further examples of compounds embraced by the present invention or useful in the preparation of compounds of the present invention.
(2R,4R)-Methyl-2-tert-butyl-1,3-thiazoline-3-formyl-4-carboxylate.
(2R,4R)-Methyl-2-tert-butyl-1,3-thiazoline-3-formyl-4-methyl-4-carboxylate.
S-[2-[[(1-Dimethylethoxy)carbonyl]amino]ethyl]-2-methyl-L-cysteine trifluoroacetate.
(S)-1-[(Benzyloxycarbonyl)amino]-2-propanol.
(S)-1-[(Benzyloxycarbonyl)amino]-2-propanol tosylate.
S-[(1R)-2-(Benzyloxycarbonylamino)-1-methylethyl]-2-methyl-L-cysteine trifluoroacetate.
S-[(1R)-2-Amino-1-methylethyl]-2-methyl-L-cysteine hydrochloride.
S-(2-Aminoethyl)-L-cysteine, methyl ester.
N-(4-Chlorophenyl)methylene]xe2x80x94Sxe2x80x94[2-[[(4-chlorophenyl)methylene]amino]ethyl]-L-cysteine, methyl ester.
N-[4-Chlorophenyl)methylene]xe2x80x94Sxe2x80x94[2-[[(4-chlorophenyl)methylene]amino]ethyl]-2-methyl-D/L-cysteine, methyl ester.
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.